Pancreatic cancer is the fifth leading cause of cancer death in the US. Despite tremendous efforts aimed at understanding its molecular biology, conventional treatment has had little impact. Due to the highly metastatic nature of the disease, surgery is available to only 15- 20% of patients. Thus, the development and characterization of new therapeutic agents that can be used alone or together with conventional therapies is desperately needed. There are 4 classes of HDACs, and it is hypothesized that increased HDAC activity in cancer cells may contribute to the epigenetic silencing of tumor suppressor genes such as p16, p21 and gelsolin. In fact, treatment of pancreatic cancer cells with the broad spectrum classI/II HDAC inhibitor (HDACI), SAHA, leads to upregulation of p21, growth inhibition and induction of apoptosis. The team of Professor Kozikowski at UIC has recently generated novel classes of HDACIs, several of which show low pM activity toward HDAC6 and HDAC3 in vitro. Treatment of pancreatic cancer cells with these compounds results in a G1 and/or G2 arrest and induction of apoptosis. In addition, the data indicate that some of these novel HDACIs cause loss of the DNA damage checkpoint kinase, Chk1. It is hypothesized that they can sensitize pancreatic tumor cells to genotoxic agents. We believe that a combination of these HDACIs with DNA damage-inducing agents, such as gemcitabine, will provide significant therapeutic benefit compared to the conventional treatment, gemcitabine alone. To test this hypothesis, we propose to (1) re-synthesize the 12 most active HDACIs made at UIC, and to synthesize 10 new analogs and test them for isoform selectivity;(2) to define biological effects of HDACIs on pancreatic tumor cell proliferation and survival in vitro;and (3) to determine the in vivo efficacy of the 5 best HDACIs on established pancreatic tumor cell line xenografts with co-administration of gemcitabine. These studies will provide important information regarding the use of HDACIs in combination with therapeutic agents that cause DNA damage, and valuable structure-activity relationship (SAR) data relevant to the safety and efficacy of these compounds in the treatment of pancreatic cancer, while allowing to gauge the extent to which isoform selectivity is required in finding a "safe" therapy. The biological characterization of the HDACIs presented herein may also allow to better link specific isoforms to tumorigenic events. The two or three best HDACIs identified in this Phase I proposal will be the subject of a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fifth leading cause of cancer death in the US and is poorly treatable by conventional chemotherapy, while surgery is available to only 15-20% of patients due to the highly metastatic nature of the disease. The present application aims at investigating the ability of a novel series of inhibitors of histone deacetylases (HDACs), which have been shown to inhibit pancreatic cancer cell growth in vitro and lead to apoptosis, to inhibit the growth of pancreatic tumor cell line xenografts in mice in combination with the conventional chemotherapeutic agent, gemcitabine. Positive results would lead to a Phase II application to fund ADMET work aimed at advancing one of these compounds into clinical studies.